EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2.
EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2.
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EphA2超级增强子通过招募FOSL2和TCF7L2来激活靶基因EphA2，从而促进肿瘤进展。
DOI：
10.1038/s41419-021-03538-6
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发表时间：
2021-03-12
影响因子：
9
通讯作者：
He H
中科院分区：
文献类型：
--
作者：
Cui S;Wu Q;Liu M;Su M;Liu S;Shao L;Han X;He H
超级增强子或延伸增强子（SE）由大簇的活性转录增强子组成，其促进在发育和疾病期间限定细胞身份的关键基因的表达。然而，许多超级增强子在肿瘤细胞中的作用仍不清楚。本研究旨在探讨一种新的超级增强子在多种肿瘤细胞中的作用和机制。使用多个数据库发现了一种存在于多种肿瘤中的新的超级增强子，称为EphA 2-Super-enhancer（EphA 2-SE），并进一步鉴定。CRISPR/Cas9介导的EphA 2-SE缺失导致其靶基因EphA 2的显著下调。从机制上讲，我们发现EphA 2-SE的核心活性区包含E1组分增强子，其募集TCF 7 L2和FOSL 2转录因子来驱动EphA 2的表达，诱导细胞增殖和转移。RNA-seq数据的生物信息学分析和体外功能实验表明，EphA 2-SE缺失通过阻断HeLa、HCT-116和MCF-7细胞中的PI 3 K/AKT和Wnt/β-catenin通路来抑制细胞生长和转移。EphA 2-SE-/-克隆中EphA 2的过表达挽救了EphA 2-SE缺失对增殖和转移的影响。随后的异种移植动物模型显示EphA 2-SE缺失抑制了体内肿瘤增殖和存活。总之，这些发现表明EphA 2-SE通过募集FOSL 2和TCF 7 L2来驱动癌基因EphA 2的表达，在各种肿瘤中发挥致癌作用并促进肿瘤进展。
Super-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE−/− clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.
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8
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11.4
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影响因子：
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